Strabismus, binocular misalignment, is prevalent and usually treated surgically with imperfect outcomes. This is the predictable result of inadequate understanding of extraocular muscle (EOM) innervation, orbital anatomy, and the biomechanics of binocular alignment, sometimes leading to erroneous diagnoses and surgery. Orbital connective tissues, including pulleys, form a complex system influencing binocular alignment and kinematics of all eye movements. Congenital and acquired pulley abnormalities cause some types of strabismus, and others may be related to manipulations of pulleys during strabismus surgery. We propose a multidisciplinary approach to understanding the mechanics of eye movement through parallel studies in humans and animals, and how EOM pulling directions are altered by vestibulo-ocular reflexes. We will employ magnetic resonance imaging (MRI) to visualize EOMs and connective tissues as they change with gaze direction and otolith influences in normal and strabismic subjects. We will investigate in humans these functional anatomical changes in otolith-dependent strabismus, pulley disorders, and following performance of emerging surgical manipulations of pulleys. We will investigate and mathematically model the kinematic effects of pulleys, including effects of vestibularly-mediated eye torsion on rectus EOM pulling directions, non-insertional force coupling from pulleys to the globe, and effects of pulley abnormalities on conformity to Listing's Law. We will employ MRI to study directly in living humans the effects of acquired and genetically characterized congenital cranial neuropathies on EOMs, EOM innervation, and binocular alignment. In complimentary experiments in genetically modified mice, we will microscopically study EOM, connective tissues, and nerve phenotypes of mutations causing the congenital forms of strabismus we will investigate in humans. Relevance: This project aims to clarify understanding of muscles and ligaments responsible for keeping the two eyes aligned for single vision. This understanding will improve diagnosis and surgical treatment of crossed and deviated eyes, common problems leading to double vision and visual loss. Studies will also clarify basic genetic and mechanical causes of abnormal eye movements, balance disorders, and aid development of newly-emerging surgeries for treating strabismus.